The long-term objectives of the applicant involve the integration of clinical stereotactic neurosurgery and radiosurgery with pertinent clinical and laboratory research that examines the effects of single- session, precise, small-volume irradiation for brain tumors and vascular malformations. The applicant uses in vivo radiobiologic studies to investigate normal brain response and protection, and to study in vivo tumor responses. Prospective randomized clinical trials are used to investigate the medical and economic benefits of radiosurgery in comparison to conventional open neurosurgery or to conventional radiotherapy. The physiologic and histologic response of cranial nerves to high radiation doses must be determined because radiosurgery is used often for lesions at the skull base. A dose-response relationship for optic chiasm radiation sensitivity is determined after radiosurgery targeted to the rat optic chiasm (doses, 6-lOO Gy). Serial visual evoked potentials are performed followed by histologic analysis after one year. High-dose pentobarbital is studied as a radiation protector for single-fraction irradiation in the rat frontal lobe model. Rats are randomized to lOO Gy doses either under pentobarbital anesthesia for brain protection, or under ketamine anesthesia without protection. The brain response is determined at intervals from 60-365 days. An in vivo rat malignant glioma model is used to determine the effects of radiosurgery in combination with whole brain irradiation or sensitizing agents. Rats are randomized to a control group, radiosurgery (70 Gy, 14 days after implantation), radiosurgery plus whole brain fractionated radiotherapy (20 Gy), and radiosurgery plus a radiation sensitizer. Histologic effects, growth in cell culture, and changes in growth factor production are determined. An in vivo sub-renal capsule athymic mouse xenograft model is used to determine long-term histologic effects and effects on cell growth in culture. A prospective randomized trial evaluates stereotactic radiosurgery plus whole brain fractionated radiotherapy versus fractionated radiotherapy alone for the management of patients with multiple brain metastases. Patients with 2-4 metastatic tumors, each less than 25 mm in diameter, are randomized and studied in regard to local tumor control (tumor volume) and patient survival. Through these investigations, the applicant plans to clarify indications for radiosurgery and improve procedural results. Laboratory studies are designed to be of clinical importance and to stimulate concurrent work at other institutions so that long-term objectives within this proposal are sought on a national level.